C.239 GA: From Uncertain Significance to a Pathogenic Variant in a Colombian Family Cluster

Background: Fabry disease (FD) is a rare inherited lysosomal storage disease which affects men and women of all ethnicities and is caused by deficient alpha-galactosidase A, leading to the accumulation of globotriaosylceramide in different tissues and organs (1-3). It has a variety of symptoms, which can be quite heterogeneous in terms of presentation and severity, affecting different systems and organs. Moreover, it is challenging for clinicians trying to interpret GLA variants as more than 1000 variants of uncertain significance (VUS) have been identified, leading to late diagnosis.

Methodology: Cross-sectional descriptive observational study of a cohort from a family cluster with an FD-confirmed diagnosis, in which the clinical symptoms and principal biomarkers were registered and analysed.

Results: The cohort of 15 mostly male patients with Fabry disease and a c.239 GA (G80D) mutation had a median age of 36 years and were from three different cities in Colombia. Most patients presented varied symptoms including exercise intolerance (12/15; 80.00%) and fatigue (14/15; 93.33%). The average α-galactosidase A was 3.25 µmol/L/H and Lyso Gb3 was 2.09 µmol/L/H (ranges considered normal). The most prevalent renal alteration was related to a moderately increased albuminuria/creatinuria ratio (average of 53.53 mg/g), while the most prevalent cardiac alteration was an increased left ventricular mass in some patients even though the average left ventricular ejection fraction (LVEF) was within normal limits (63%) in most patients, which fits with the traditional manifestations of the pathogenic variant of FD. Visual and hearing symptoms were less frequent with one patient (7.14%) having a cataract, two patients (15.38%) with cornea verticillata, one patient (6.67%) with tinnitus and three patients (20%) with hearing loss. The most frequent gastrointestinal symptom was abdominal pain (10/15; 66.67%). Regarding neuropsychiatric symptoms, the most frequent symptom was anxiety (8/15; 53.33%), followed by depression (7/15).

Conclusion: Disease heterogeneity and the wide genetic variability among different populations could lead to a delayed diagnosis, so it is necessary to understand the local and individual behaviour of genetic variants. For this, databases should be created to establish population characteristics of rare/low-incidence diseases to accelerate diagnosis and treatment opportunities.